Our long-term objective is to understand the molecular genetics of hereditary human retinal diseases, such as retinitis pigmentosa (RP) and age-related macular degeneration (AMD). Our approach is to use Drosophila as a model system. Human RP and AMD are highly complex diseases with multiple subtypes, each with a distinct genetic and biochemical basis. This complexity, along with the limited availability of suitable tissues from RP and AMD patients and the broad base of knowledge of Drosophila genetics, combine to make Drosophila a powerful animal model for studying inherited retinal degeneration disorders. Our research is focused on those events during protein biosynthesis in the secretory pathway that ensure correct protein translocation, glycosylation, folding, oligomeric assembly, quality control, transport and targeting. The endoplasmic reticulum (ER) contains a wide variety of molecular chaperones, folding sensors and enzymes, as well as escort proteins that facilitate the early stages of protein biosynthesis. Upon exiting the ER, newly folded proteins must be transported to the Golgi, where they undergo a new set of modifications that proceed sequentially from the cis- to the medial-, and finally to the trans- compartments of the Golgi. Transport of proteins between compartments of the secretory pathway occurs via the budding and fusion of small vesicles from donor compartments to target compartments. Vesicular transport is facilitated by a vast array of cytosolic and membrane bound factors, such as GTP-binding proteins (Rabs), coat components, motor proteins, tethering molecules, and finally SNAREs (soluble N- ethylmaleimide-sensitive factor attachment protein receptor). In this application we are specifically focused on two major aspects of protein biosynthesis and transport: (1) The SNARE proteins and their role in vesicular transport of rhodopsin and other constituents of phototransduction, and (2) the family of mannosidases and their key roles in trimming carbohydrates in the ER and Golgi during rhodopsin biosynthesis. Given that the SNARE proteins and mannosidase enzymes investigated here are highly conserved in humans, our findings in Drosophila should be readily applied to human processes and diseases. Accordingly, our discoveries in Drosophila will be used to screen a highly defined set of human AMD and RP pedigrees for similar defects. We anticipate that this work will greatly impact our understanding of the fundamental mechanisms of protein trafficking and also provide important insights into retinal diseases such as RP and AMD.